WO2007124598A2 - Capsules gélatineuse molle - Google Patents

Capsules gélatineuse molle Download PDF

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Publication number
WO2007124598A2
WO2007124598A2 PCT/CA2007/000747 CA2007000747W WO2007124598A2 WO 2007124598 A2 WO2007124598 A2 WO 2007124598A2 CA 2007000747 W CA2007000747 W CA 2007000747W WO 2007124598 A2 WO2007124598 A2 WO 2007124598A2
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phytosterols
esters
phytostanols
omega
fatty acids
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PCT/CA2007/000747
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English (en)
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WO2007124598A3 (fr
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David John Stewart
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Forbes Medi-Tech Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/286—Carthamus (distaff thistle)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/42—Cucurbitaceae (Cucumber family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/55—Linaceae (Flax family), e.g. Linum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • This present invention relates to the field of nutraceuticals, particularly softgel capsules, comprising phytosterol and phytostanol esters.
  • Atherosclerosis is a degenerative process resulting from an interplay of inherited (genetic) factors and environmental factors such as diet and lifestyle.
  • CVD cardiovascular disease
  • Research to date suggest that cholesterol may play a role in atherosclerosis by forming atherosclerotic plaques in blood vessels, ultimately cutting off blood supply to the heart muscle or alternatively to the brain or limbs, depending on the location of the plaque in the arterial tree 1 , 2 .
  • Data from the early Framingham Epidemiological Study indicates that increases in serum cholesterol levels are associated with increased risk of death from CVD 3 . More recent studies confirm that CVD is a leading cause of death and disability in industrialized nations 4 .
  • plant-derived sterols and stanols also known as phytosterols and phytostanols.
  • Sterols are naturally occurring compounds that perform many critical cellular functions.
  • Phytosterols such as campesterol, stigmasterol and beta-sitosterol in plants, ergosterol in fungi and cholesterol in animals are each primary components of cellular and sub-cellular membranes in their respective cell types.
  • the dietary source of phytosterols in humans comes from plant materials i.e. vegetables and plant oils.
  • the estimated daily phytosterol content in the conventional western-type diet is approximately 60-80 milligrams in contrast to a vegetarian diet which would provide about 500 milligrams per day.
  • Phytosterols have received a great deal of attention due to their ability to decrease serum cholesterol levels when fed to a number of mammalian species, including humans. While the precise mechanism of action remains largely unknown, the relationship between cholesterol and phytosterols is apparently due in part to the similarities between the respective chemical structures (the differences occurring in the side chains of the molecules). It is assumed that phytosterols displace cholesterol from the micellar phase and thereby reduce its absorption or possibly compete with receptor and/or carrier sites in the cholesterol absorption process.
  • phytosterols Despite the obvious and now well recorded advantages of phytosterols, not only in the treatment of CVD and its underlying conditions such as hypercholesterolemia, hyperiipidemia, atherosclerosis, hypertension, thrombosis but in the treatment of other diseases such as Type Il diabetes, dementia cancer and aging, the administration of phytosterols and the incorporation thereof into foods, pharmaceuticals and other delivery vehicles has been complicated by the fact that they are highly hydrophobic (i.e. they have poor water solubility). This highly hydrophobic nature of phytosterols renders them insoluble and barely dispersible in aqueous media. As such, phytosterols tend to be added to the fat phase of fat-based food products. Health-conscious consumers wishing to benefit from the cholesterol lowering effects of phytosterols are therefore forced to consume fat- rich foods, despite the health risks of a high fat diet.
  • phytosterols have a waxy consistency and a high melting point, creating solubility issues for the food processor. While they are oil-dispersible to some extent in their raw form, the amount required to produce an efficacious effect in a finished product can cause granulation.
  • esters are not liquid or pourable at room temperature. As such, in any process of manufacturing capsules, esters must be heated to above 35-40 0 C during or prior to filling into the capsules. In reality, in order to avoid solidification in the encapsulation equipment, the ester temperature needs to be maintained at or above 40-50°C.
  • Phytosterol/stanol esters are usually sold and transported in 180 kg or larger size containers.
  • the time required to bring a 180kg barrel of esters to 40-50 0 C is 3 to 6 days with specific heating equipment being required.
  • phytosterol/stanol esters are highly viscous and are not readily amenable to softgel economic softgel capsule processing.
  • the present invention provides a composition for use in softgel capsules comprising one or more esters of phytosterols and/or phytostanols which have been treated to enhance their flowability at ambient temperatures prior to or concurrent with softgel formation.
  • the present invention provides a composition for use in softgel capsules comprising one or more esters of phytosterols and/or phytostanols which have been treated to reduce their viscosity at ambient temperatures.
  • the present invention provides a composition for use in softgel capsules comprising one or more esters of phytosterols and/or phytostanols which have been pre-mixed with an edible oil prior to softgel capsule formation in order to enhance the flowability of the esters at ambient temperatures.
  • the present invention provides a composition for use in softgel capsules comprising one or more esters of phytosterols and/or phytostanols which have been pre-mixed with an edible oil comprising omega polyunsaturated fatty acids prior to softgel capsule formation in order to reduce the viscosity of the esters at ambient temperatures.
  • the present invention further provides softgel capsules comprising one or more esters of phytosterols and/or phytostanols which have been treated to enhance their flowability at ambient temperatures prior to or concurrent with softgel formation.
  • the present invention further provides a method of stabilizing from oxidation a composition of one or more esterified phytosterols and phytostanols such composition being useful for softgel capsule filler, which comprises solubilizing in the esters one or more free (unesterified) phytosterols or phytostanols.
  • the present invention further provides a method of stabilizing from oxidation a composition of one or more esterified phytosterols and phytostanols such composition being useful for softgel capsule filler, which comprises mixing the ester with an edible oil into which has been solubilised one or more free (unesterified) phytosterols or phytostanols.
  • the edible oil preferably as described below, is high in omega polyunsaturated fatty acids, decreases the viscosity of the esters and enhances their handling and pourability.
  • the free sterols/stanols, solubilised within the ester, have been found to decrease the oxidation of the esters thereby increasing the useful life the capsule.
  • free sterols/stanols are solubilized in an edible oil, and then mixed with the ester forming a composition suitable for softgel filler.
  • the free, unesterifed phytosterols and phytostanols can readily be dissolved in phytosterol and/or phytostanol esters by heating the mixture to approximately 90 0 C.
  • the free phytosterols/stanols remain dissolved once the mixture is cooled.
  • This dissolution in the esters presents a number of advantages.
  • the edible oil also reduces the melting point of the esters, so that the composition becomes fluid at room temperature, eliminating the need for special warming equipment thereby saving significantly on softgel capsule manufacturing costs. This is a critical advantage which not only assists in manufacturing but reduces materials loss, due to room temperature flowability.
  • the softgel capsules of the present invention have an enormous number of therapeutic uses when administered to animals, in particular humans, not only in respect to the treatment of cardiovascular disease and its underlying conditions such as hypercholesterolemia, hyperlipemia, atherosclerosis, hypertension, thrombosis but in the treatment and inhibition of other diseases such as Type Il diabetes, dementia (including Alzheimer's disease), neural degeneration, cancer (including colon and prostate), and mental disorders such as bipolar disease.
  • the softgel capsules may be used to enhance brain development and visual acuity.
  • animal means any member of the animal kingdom, including preferably humans.
  • the term “phytosterol” includes all sterols without limitation, for example: sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, pollinastasterol, and all natural or synthesized forms and derivatives thereof, including isomers.
  • phytostanol refers to saturated or hydrogenated sterols including all natural or synthesized forms and derivatives thereof, and isomers. It is to be understood that modifications to the phytosterols and phtostanols i.e. to include side chains also falls within the purview of this invention. For example, the purview of this invention clearly includes 24 beta- ethylsitostanol, 24-alpha-ethyl-22-dehydrositostanol. It is also to be understood that, when in doubt throughout the specification, and unless otherwise specified, the term “phytosterol” encompasses both sterol and stanol. In a most preferred form, the sterol is in its saturated form and is a sitostanol, preferably beta-sitostanol.
  • sterols and stands for use in accordance with this invention may be procured from a variety of natural sources.
  • plant oils including aquatic plants
  • plant oils such as com oil and other vegetable oils, wheat germ oil, soy extract, rice extract, rice bran, rapeseed oil, sunflower oil, sesame oil and fish (and other marine-source) oils.
  • plant oils including aquatic plants
  • They may also be derived from fungi, for example ergosterol.
  • the present invention is not to be limited to any one source of sterols.
  • US Patent Serial No. 4,420,427 teaches the preparation of sterols from vegetable oil sludge using solvents such as methanol.
  • phytosterols and phytostanols may be obtained from tall oil pitch or soap, by-products of forestry practises as described, for example, in US Patent Serial No.5,770,749, incorporated herein by reference.
  • Phytosterols and phytostanols may be in their free form or in one or more of their esterified forms i.e. optionally, the phytosterol or phytostanol may be esterified prior to formation of the food products. This esterification step renders the phytosterols and/or phytostanols more soluble in fats and oils which may, in some instances, facilitate the incorporation of the phytosterols into various food products.
  • phytosterol and/or phytostanol esters many methods are known in the art.
  • one or more suitable aliphatic acids or their esters with low boiling alcohols may be condensed with the selected phytosterol and/or phytostanol.
  • a wide variety of aliphatic acids or their esters may be used successfully and include all aliphatic acids consisting of one or more alkyl chains with one or more terminal carboxyl groups. These aliphatic acids may be natural of synthetic and are represented by the following chemical formulae:
  • R1 is an unbranched saturated alky group, represented by CH3-, CH3CH2- or
  • HOOC-R2-COOH is a dicarboxylic acid wherein:
  • a mono-, di-, or tricarboxylic acid as defined above which may contain one, two or three hydroxyl groups in the molecule.
  • the acid is either a straight-chain or branched unsaturated or saturated, aliphatic or aromatic acid. More preferably, the acids are selected, inter alia, from the following list: valeric acid, isovaleric acid, sorbic acid, isocaproic acid, lauric acid, myrestic acid, palmitic acid, stearic acid, caproic acid, ascorbic acid, arachidic acid, behenic acid, hexacosanoic acid, octacosanoic acid, pentadecanoic acid, erucic acid, linoleic acid, linolenic acid, arachidonic acid, acetic acid, citric acid, tartaric acid, palmitoleic acid and oleic acid.
  • valeric acid isovaleric acid
  • sorbic acid isocaproic acid
  • lauric acid myrestic acid
  • palmitic acid palmitic acid
  • stearic acid caproic acid
  • fatty acids within the scope of the present invention are linoleic acid, linolenic acid and arachidonic acid which may be obtained from natural sources such as safflower oil, sunflower oil, olive oil and com oil (linoleic acid), safflower oil, sunflower oil, olive oil and jojoba oil (linolenic acid and arachidonic acid) and rapeseed oil (erucic acid).
  • the sterol and stanol esters may be formed with fatty acids selected from: eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and alpha-linolenic acid (ALA).
  • the selected phytosterol and acid or its ester with volatile alcohol may be mixed together under reaction conditions to permit condensation of the phytosterol with the acid.
  • a most preferred method of preparing these esters which is widely used in the edible fat and oil industry is described in US Patent Serial No. 5,502,045 (which is incorporated herein by reference).
  • a fatty acid ester or mixture thereof and an interesterification catalyst like sodium ethylate are used, the technique is highly suitable for preparing products ultimately for human consumption.
  • this preferred method comprises heating the phytosterol(s) with a vegetable oil fatty acid ester (preferably a methyl ester) at a temperature from 90-120 0 C and subsequently adding a suitable catalyst such as sodium ethylate.
  • a suitable catalyst such as sodium ethylate.
  • the catalyst is then removed/destroyed by any one of the techniques known in the art e.g. adding water and/or filtration/centrifugation.
  • phytosterol ester and phytostanol ester as used herein, including, but not limited to: esterified phytosterols and phytostanols with aliphatic or aromatic acids (thereby forming aliphatic or aromatic esters, respectively), phenolic acid esters, cinnamate esters, and ferulate esters.
  • phytosterols as used herein, whether singular or plural, unless otherwise indicated, includes both phytosterols and phytostanols.
  • the composition of the present invention useful as a "filler" for use in softgel capsules comprises a ratio of omega polyunsaturated fatty acid oil to sterol/stanol esters from about 5:1 to 30:1. In a further preferred form, the composition comprises a ratio of omega polyunsaturated fatty acid oil to sterol/stanol esters from about 1:5 to 1 :20. Whether significantly more sterol/stanol ester or omega PUFA oil is present in the capsule depends largely on the therapeutic indication to be treated or prevented.
  • the capsules comprise significantly more omega polyunsaturated fatty acid oil than esters than would be preferred in capsules for the treatment of cardiovascular disorders. This is apparent from the examples provided hereinbelow.
  • the present invention includes:
  • softgel capsules comprising one or more esters of phytosterols and/or phytostanols and component to enhance the flowability of the esters.
  • softgel capsules comprising one or more esters of phytosterols and/or phytostanols and component to reduce the viscosity of the esters at ambient temperatures.
  • softgel capsules comprising one or more esters of phytosterols and/or phytostanols and a measurable amount of one or more free phytosterols and/or phytostanols.
  • softgel capsules comprising one or more esters of phytosterols and/or phytostanols and an edible oil.
  • softgel capsules comprising one or more esters of phytosterols and/or phytostanols a measurable amount of one or more free phytosterols and/or phytostanols and an edible oil.
  • any of the above softgel capsules comprising omega-3, omega-6 and/or omega-9 polyunsaturated fatty acids.
  • the composition comprises from 1-15% by weight unesterified phytosterol and/or phytostanol substantially completely dissolved in 85-99% by weight of one or more esterified phytosterols and/or phytostanols. In a further preferred form, the composition comprises from 4-8% by weight unesterified phytosterol and/or phytostanol substantially completely dissolved in 92-96% by weight of one or more esterified phytosterols and/or phytostanols.
  • the composition for use in forming the softgel capsules comprises an edible oil to which the free (unesterifed) phytosterols and/or phytostanols are added prior to the substantially complete dissolution in the esterified phytosterols and/or phytostanols.
  • the edible oil may be selected from but is not limited to the group consisting of olive, rapeseed, canola, sunflower, safflower, sesame, soyabean, corn, coconut, peanut, cottonseed, hemp, flaxseed, and pumpkinseed.
  • the edible oil selected is high in one or more of omega 3 polyunsaturated fatty acids, omega 6 polyunsaturated fatty acids and omega 9 polyunsaturated fatty acids.
  • Such an addition of edible oil reduces the melting point of the esters, so that the composition becomes and stays fluid at room temperature, thereby completely eliminating the need for special warming equipment during processing of the esters.
  • omega-fatty acids are known to reduce the build up of atherosclerotic plaque in the arteries (Von Schacky.2000; Erkkila.2004;Renier.1993).
  • the omega fatty acids act by mechanisms independent of the reduction in LDL. They have anti-oxidant activity (Frenoux.2001 ) and anti-inflammatory activity (Maroon.2006) and can raise HDL (good cholesterol) levels and may contribute to reduction in atherosclerotic plaque formation by these mechanisms.
  • Omega fatty acids also have anti-coagulant properties (Schmidt.2001 ; Mori.2003).
  • omega-3-fatty acids have the undesirable effect of raising blood LDL in the human (Harris.1996; Theobald.2004). The effect may be related to the anti-oxidant effect of omega-3-fatty acids (Kraus.2004). However, when omega-3-fatty acids are combined with phytosterols, this side effect is eliminated, while still maintaining maximum efficacy of the phytosterols in reducing blood LDL reductions. In addition, omega fatty acids have additional synergistic and protective effects against cardiovascular disease not provided by phytosterols. Omega fatty acids have been demonstrated to reduce triglycerides (Roche.1996) and blood pressure (Frenoux.2001 ;Prisco.1998), two additional risk factors for heart disease.
  • the combination within the softgel capsules may have other synergies as well. It is now recognized that lifestyle changes or treatments that reduce the risk of cardiovascular disease also reduce the risk of Alzheimers Disease (Luchsinger.2004). FDA has allowed a health claim for phytosterols "may reduce the risk of coronary heart disease” (FDA#1 ). The same but qualified claim may also be made for omega-3-fatty acids from a fish source (FDA#2). Tall oil phytosterols ( ⁇ -sitosterol) have been demonstrated to reduce the symptoms of benign prostate hypertrophy (Berges.2000; Coleman.2002). The effective dose of sitosterol is in the range of 20 to 60 mg per day.
  • omega-3-fatty acids For supplements, 2g/day of fish source omega-3-fatty acids is the top end of the allowed range in the US.
  • the FDA has set the upper limit for supplements at 2g/day of omega-3- fatty acids (FDA letter of October 2000). Because the effects of omega-3-fatty acids are multiple, the dosage targeted depends on what is being claimed.
  • omega-3-fatty acids reduce the blood levels of triglycerides. This has benefit in protecting against pancreatitis associated with certain medications, diabetes, and excessive alcohol intake (Pejic.2006). In the EU, a dose of 1.5 g/day qualifies for the claim "helps control levels of triglycerides".
  • a dose 1.0g/day qualifies for the claim “helps to reduce serum triglycerides”. Elevated levels of triglycerides contribute to the development of Type 2 diabetes, a major risk factor for heart disease. In large secondary prevention studies, doses of omega-3-fatty acids (0.5g -1.8g/day) have been demonstrated to reduce the risk of heart attacks, sudden death, and all-cause mortality. American Heart Association statement (Kris-Etherton, 2002). In Canada, a dose of >0.5g/day qualifies for the claim "helps maintain/support cardiovascular health". In the EU, a dose of >0.450 g/day of long chain omega-3-polyunsaturated acids qualifies for the claim "helps maintain heart health". Examples of capsules with 2g/day omega-3-fatty acids (high dose) are found in Tables 2,3, 1.0g/day (medium dose)in Tables 4,5,8 and 0.5 g/day (low dose) in Tables 6,7.
  • Alzheimers Disease Combination Of Phytosterols With Omega-3-Fatty Acids
  • Alzheimer's disease is the most common form of dementia and currently affects over 13 million people worldwide. The direct and indirect cost of Alheimer's disease care is over $100 billion in the US alone. A number of studies have shown that fish source omega-3- fatty acids can delay cognitive decline in the elderly (Beydoun.2007). The onset of Alzheimers disease is also associated with abnormalities in cholesterol metabolism, elevated cholesterol levels, and atherosclerosis. There is some evidence of a significantly reduced incidence of Alzheimer's disease among people who have been using statins to reduce hypercholesterolaemia and its cardiovascular effects (Whitfield.2006). Similarly, phytosterols by reducing LDL cholesterol levels, may have the same effect.
  • a combination of phytosterols and omega-3-fatty acids is therefore expected to have an added benefit to that of omega-3-fatty acids in delaying the onset of Alzheimer's disease.
  • Tables 2-5 provide examples of formulations with high sterol dosages and high or moderate omega- 3-fatty acid doses. These may have effect on cognitive decline and the onset of Alzheimers disease.
  • the softgel capsules within the scope of the present invention, allow the optimal delivery of sterols and omega.
  • Tocotrienols are natural inhibitors of cholesterol synthesis and act by post-transciptional inhibition of HMG CoA reductase (Song.2006).
  • the optimum dose observed for lowering LDL cholesterol in the human was reported to be 100 mg/day (Quershi et al 2002).
  • Tocotrienols like phytosterols (Mohammed.1997) and omega-3-fatty acids (Erkkila.2004) protect against atheroma formation (Black.2000). Because phytosterols and tocotrienols act by different mechanisms, the effects on LDL cholesterol will be additive. Two examples of phytosterol/tocotrienol combinations are found in the Table below.
  • the softgel capsules within the scope of the present invention, allow the optimal delivery of sterol, omega and tocotrienols.
  • Changing blood levels of endogenous phytosterols in the blood may have negative effects on health. Blood levels and intakes of phytosterols are higher in individuals eating a vegetarian diet. This type of diet is associated with a lower risk of heart disease. Low doses of tall oil sterols (sitosterol) has been shown to be effective in reducing the symptoms of benign prostate hypertrophy (Berges.2000; Coleman.2002), a condition that affects the majority of males over the age of 40. There are individual differences in the degree to which phytosterols are absorbed from the diet. There is a positive correlation between blood levels of phytosterols and the development of atherosclerosis (Glueck.1991) and coronary events (Assmann.2006).
  • the free sterol/stanol component comprise from 10 to 25 wt % free stanols, more preferably from 15-20 wt % (the remainder, of course, being free sterols).
  • Tall oil sterols, as extracted from the source generally have an endogenous content of stanols of about 9 to 12% (stanols are usually undetectable in vegetable oil sterols).
  • stanols be spiked or blended into the endogenous, extracted composition in order to achieve the preferred, higher concentration of stanols.
  • the amount of free sterols/stanol be below 40%wt of the fill weight of the capsule. It is preferred, although not required, that the amount of ester be above 20% of the fill weight of the capsule. Exceptions to this include capsules for use in treating prostate disorders, as shown more fully in the examples below.
  • vegetable oil is used as the diluent for the ester.
  • the reduced viscosity of the mixture may result in non-uniformity in the fill mixture.
  • a higher viscosity vegetable oil such as olive oil can be used in this situation. It is fully within the purview of a skilled person in this area to sleet oils which address such viscosity issues.
  • Tables 10 and 11 present examples of sterol only formulations.
  • Softgel Capsules Formation The creation and commercial manufacture of softgel capsules is well know in the art, and is not described in detail herein.
  • the formulations and pharmaceutical compositions can be prepared by these known, conventional techniques. Additional, pharmaceutically available excipients and additives can be included, as desired.
  • Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavourings, thickeners, colouring agents, emulsifiers and the like.
  • the capsules include push-fit capsules made of, for example, gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • a plasticizer such as glycerol or sorbitol.
  • stabilizers may be added.
  • Non-animal gelatin equivalents may be substituted.
  • capsule size A number of considerations need to be taken into account when manufacturing capsules.
  • the upper size limit which most consumers find acceptable is about 1.20 g, a size commonly used for fish oil supplements.
  • the second consideration is the number of capsules needed to be taken per day. As a matter of practicality, the upper limit is 4 to 6 capsules per day. At the larger capsule size, an oblong shape (1000 mg or more) is preferred as this is easier to swallow.
  • the present invention is not limited by these parameters.
  • Phvtosterols The number of portions per day of phytosterol containing products is regulated in the United States and in the European Union.
  • the FDA health claim for phytosterols requires two servings per day (FDA#1 ).
  • the European Union requires that phytosterols be dosed in either one portion per day or three portions per day but not two portions (EU labelling regulation). Another consideration is the minimum dose needed for efficacy.
  • the FDA has set this dose at 0.8 g/day.
  • the European Union has not set a minimum dose, but has set a maximum allowable dose of 3.0 g/day.
  • Studies done with the applicant's proprietary tall oil sterols show that a near maximal lowering of LDL occurs at a dose of 1.8 g/day when taken with meals three times a day.
  • the preferred dosage for lowering LDL cholesterol is 1.8 g per day in divided doses.
  • Omega-3-fatty acids The FDA recommends that supplement products be labelled to deliver less than 1 g/day (FDA #2). The FDA recommends an upper limit of 3g/day for intake from supplement products and foods. The American Heart Association recommends a daily intake of 500 - 1800 mg/day of omega-3-fatty acids from supplements and fish sources.
  • the capsule fill volumes have been kept below 1200 mg by increasing the number of capsules required per day to provide the indicated dosage.
  • the content of sterol esters have been kept above 20% of the fill weight and the content of free sterols/stanols has been kept below 40% to avoid the problem of re-crystallization of the sterols/stanols below the capsule shell.
  • Exceptions are examples 34 and 35 where the sterol content is low enough to dissolve in the lipid fraction.
  • the examples where there is a high proportion of the fill as omega-3-fatty acids it may be necessary to add a thickening agent to maintain the free sterols/stanols in suspension during the capsule filling operation. With higher proportions of sterol esters, this is unnecessary.
  • the relative proportions of sterols and omegas depends on the market. If the consumer views the omega-3-fatty acid content as the more important parameter, formulations as shown in Tables 2, 3 and 9 might be preferred.
  • the cholesterol reduction claim for sterols is much stronger in the United States; it is a full claim.
  • the omega fatty acid health claim is only a qualified claim and must include the statement "Supportive but not conclusive research shows that consumption of EPA and DHA omega-3-fatty acids may reduce the risk of heart disease". If the phytosterol component is to be emphasized, there are many formulations clearly showing this preference. If the objective is maximum efficacy of both components, other formulations clearly show this.
  • the fish source omega-fatty acids have two active components, DHA and EPA. These have different activities. For example, DHA is effective in preventing certain brain disorders. Fish oil omega fatty acids are available with different ratios of DHA and EPA, these generally have a purity of about 60%. The type of oil used can be varied depending on the pu ⁇ ose of the supplement. Such is within the purview of a skilled person in this field.
  • Formulations 1-7 would be useful to reduce the risk of cancer, Alzheimer's disease or other neurodegenerative diseases.
  • the preferred mixture would be formulation 5.
  • Formulations 8 and 9 are intended for use in ameliorating the symptoms of benign prostate hypertrophy.
  • the effective doses of sitosterol (tall oil sterols) are 20 to 60 mg per day.
  • Formulations 10-16 are essentially the same as formulations 3 and 4 except that the stanol content of the capsules has been increased from that typical of tall oil sterols (11.6%) to 16%, 18%, and 20%. Increasing the tall stanol content slightly reduces the volume of the fill because the amount of ester required to fill out the total dose of phytosterols is reduced.
  • Some of the preferred formulations shown relate primarily to the prevention of cardiovascular disease.
  • a cholesterol reduction claim is allowed in the United States.
  • the EU labelling regulation allows use of the statement "this product is intended only for persons who want to lower their blood cholesterol".
  • dosages of 4 and 6 capsules per day are used.
  • the health claim allows instructions based on two servings per day.
  • the EU labelling regulation requires that dosing instructions be based on either one serving per day or three servings per day but not two.
  • the 4 per day examples can be used in the United States. For example, take two capsules twice a day.
  • the 6 capsules per day examples can be used in either area. For example, in the U.S., take 3 capsules twice a day. In the EU the instruction would be take 2 capsules three times per day.
  • Formulation number 10 was tested on commercial scale encapsulation equipment with very good results. On a 50 kg batch, capsule recoveries were 95%.
  • Gelatin beef gelatin (BSE free), glycerin, water, titanium dioxide masking agent, and a light yellow colouring agent.
  • the fish oil was poured into a mixing vessel and stanols added.
  • the stanols dissolved almost immediately in omega fatty acid oil.
  • the indicated amount of sterol esters were warmed to point where the indicated amount of could be added to the mixing vessel.
  • the mixture was then encapsuled with a beef gelatin (BSE free) containing glycerin, water, titanium dioxide masking agent and a light yellow colouring agent.
  • BSE free beef gelatin
  • the capsule shape used was oblong.
  • the capsules were dried for two days at room temperature before packaging.
  • Capsules can be either animal based gelatin (beef, pork, or fish) or vegetable based gelatin. Colour and shape are optional. An off-odour sometimes comes from the animal gelatins or the fish oil. Vanillin has been found to be a good odour masking agent when incorporated into the gelatin.
  • Temp 13-15C - sticky texture viscosity less than that of, for example, honey at room temperature , therefore has a semi-high viscosity . Not able to be pumped.
  • Glueck CJ Speirs J, Tracy T, Streicher P, Wig E, Vandegrift J. Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives. Metabolism. 1991 Aug;40(8):842-8.
  • Mori Y Nobukata H, Harada T, Kasahara T, Tajima N.
  • Mozaffarian D Psaty BM, Rimm EB, Lemaitre RN, Burke GL, Lyles MF, Lefkowitz D, Siscovick DS. Fish intake and risk of incident atrial fibrillation. Circulation. 2004 JuI 27;110(4):368-73.
  • Nordoy A Marchioli R, Arnesen H, Videbaek J. n-3 polyunsaturated fatty acids and cardiovascular diseases. Lipids 2001 ;36 Suppl:S127-9 Nordoy A, Bonaa KH, Sandset PM 1 Hansen JB, Nilsen H. Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia. Arterioscler Thromb Vase Biol. 2000 Jan;20(1):259-65.

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Abstract

L'invention concerne une composition utilisée dans des capsules gélatineuses molles, comprenant un ou plusieurs esters de phytostérols et/ou de phytostanols ayant été traités pour améliorer leur aptitude à l'écoulement à des températures ambiantes avant ou simultanément à la formation de la capsule gélatineuse molle.
PCT/CA2007/000747 2006-05-01 2007-05-01 Capsules gélatineuse molle WO2007124598A2 (fr)

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US20100239660A1 (en) * 2009-03-19 2010-09-23 Doughman Scott D Product and use of omega-3s matching human tissue ratios for treatment of inflammatory and other conditions
WO2011082384A2 (fr) 2009-12-31 2011-07-07 Differential Drug Development Associates, Llc Modulation de la solubilité, de la stabilité, de l'absorption, du métabolisme et du profil pharmacocinétique de médicaments lipophiles par les stérols
WO2012049534A1 (fr) * 2010-10-14 2012-04-19 Cape Peninsula University Of Technology Complément alimentaire
US8039025B1 (en) * 2010-10-15 2011-10-18 Life Plus, LLC Methods and dosage forms for the treatment of human cancers
PE20150462A1 (es) * 2011-03-08 2015-04-06 Cognis Ip Man Gmbh Un procedimiento para la destilacion de esteres de acidos grasos
JP6537980B2 (ja) * 2013-02-28 2019-07-03 プロノヴァ・バイオファーマ・ノルゲ・アーエスＰｒｏｎｏｖａ ＢｉｏＰｈａｒｍａ Ｎｏｒｇｅ ＡＳ 脂質化合物、トリグリセリドおよび界面活性剤を含む組成物、ならびにその使用方法
CN105188670B (zh) 2013-03-15 2018-11-02 马留斯医药有限责任公司 乳液制剂
BR112017012648B1 (pt) 2014-12-22 2020-12-08 Unilever N.V composição oral ou tópica e uso de um agonista de fator nuclear eritróide 2 relacionado ao fator 2 e um agonista do receptor hepático x como agentes ativos em uma composição oral ou tópica para beneficiar o crescimento da fibra capilar e/ou induzir o elemento de resposta antioxidante (are)

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